The present invention is generally directed toward a surgical bone product and more specifically is a malleable putty containing demineralized allograft bone particles and mineralized chips and/or rods mixed in a fluid carrier having an isotonic phosphate buffer and a high molecular weight viscous excipient derived from the class of biomaterials known as hydrogels.
Surgical implants should be designed to be biocompatible in order to successfully perform their intended function. Biocompatibility may be defined as the characteristic of an implant acting in such a way as to allow its therapeutic function to be manifested without secondary adverse affects such as toxicity, foreign body reaction or cellular disruption.
Malleable bone putty is used to correct surgical defects that may be caused by trauma, pathological disease, surgical intervention or other situations where defects need to be managed in osseous surgery. It is important to have the defect filler in the form of a stable, viscous putty to facilitate the placement of the bone growth medium into the surgical site which is usually uneven in shape and depth. The surgeon will take the putty on a spatula or other instrument and trowel it into the site or take it in his/her fingers to shape the bone inducing material into the proper configuration to fit the site being corrected.
For over fifty years, surgeons have been using cancellous cubes mixed with blood and bone marrow as a form of putty. A number of premixed products presently exist to treat this surgical need. One example is autologous bone segments recovered from the patient which can be ground into bone granules. When the bone segments are removed from the patient, they are wet and viscous from the associated blood. This works very well to heal the defect but requires significant secondary surgery resulting in lengthening the surgery, extending the time the patient is under anesthesia, extending the recovery time and increasing the cost. In addition, a significant increase in patient morbidity is attendant in this technique as the surgeon must take bone from a non-involved site in the patient to recover sufficient healthy bone, marrow and blood to perform the defect filling surgery. This leads to significant post-operative pain.
Another product being used involves the use of inorganic materials to provide a matrix for new bone to grow at the surgical site. These inorganic materials include hydroxyapatite obtained from sea coral or derived synthetically. Either form may be mixed with the patient""s blood and/or bone marrow to form a putty. Calcium sulfate or plaster of Paris may also be mixed with water to similarly form a putty. These inorganic materials are osteoconductive but are bioinert and do not absorb or become remodeled into natural bone. They consequently remain in place indefinitely as a brittle, foreign body in the patient""s bone tissue.
Another prior art product is the formulation of demineralized allograft bone particles in collagen. Both bovine and human collagen have been used for this application. Bovine collagen carries the risk of an immunogenic reaction by the recipient patient. Recently, it has been found that a disease of cattle, bovine spongioform encephalopathy (BSE) can be transmitted from bovine tissue to humans. Thus, bovine tissue carries a risk of disease transmission and is not a desirable carrier for allograft tissue.
Human collagen is free of these animal based diseases. However, collagen absorbs slowly in the human body, particularly in a bony site which usually has a low degree of vascularity. The slow absorption of collagen can delay the growth of new bone and result in the formation of scar tissue at the site. This could result in a non-bony healing and a result with much less tensile strength.
Allograft bone is a logical substitute for autologous bone. It is readily available and precludes the surgical complications and patient morbidity associated with obtaining autologous bone as noted above. Allograft bone is essentially a collagen fiber reinforced hydroxyapatite matrix containing active bone morphogenic proteins (BMP) and can be provided in a sterile form. The demineralized form of allograft bone is naturally both osteoinductive and osteoconductive. The demineralized allograft bone tissue is fully incorporated in the patient""s tissue by a well established biological mechanism. It has been used for many years in bone surgery to fill the osseous defects previously discussed.
It is also well known in the art that for several decades surgeons have used a patient""s own blood as a vehicle in which to mix the patient""s bone chips or bone powder, or demineralized bone powder so as to form a defect filling paste. Blood is a useful carrier because it is available from the bleeding operative site, is non-immunogenic to the patient and contains bone morphogenic proteins which facilitate wound healing through new bone growth. However, stored blood from other patients has the deficiencies that any blood transfusion would have such as blood type compatibility, possibility of transmission of disease and unknown concentration of BMP which are to some extent dependent upon the age of the donor.
While blood contains from forty percent (40%) to fifty percent (50%) cell mass, it is a satisfactory carrier for demineralized bone powder because it contains both mono-and polysaccharides which contribute to the blood viscosity and provide the bulk viscosity to the paste created by mixing the bone powder and blood. Specific monosaccharides in blood are glucose at a concentration of 60-100 mg/100 ml (0.1%) and polysaccharides such as hexose and glucosamine at approximately 0.1%. Glucuronic acid is also present at approximately 0.4-1.4 mg/100 ml (average 0.01%).
The problems inherent with using the patients blood as a carrier for demineralized bone powder are the difficulties of mixing the same at the operating site, the difficulty in obtaining a bone paste consistency which can be easily applied to the surgical area, the guesswork in mixing a usable composition at the site and the problem of having a bone paste which will promote optimum bone replacement growth and not be carried away by the body fluids at the operation site or simply fall out of the bone defect site. In an attempt to solve these and other problems, there have been a number of other attempts using other alternative mixtures and compositions.
A number of bone defect fillers currently being used are composed of demineralized bone matrix in the form of ground bone particles or very small bone fibers. The demineralized bone matrix is mixed in a carrier such as glycerol to create a viscous mass suitable for filling bone defects.
Demineralized allograft bone is usually available in a lyophilized or freeze dried and sterile form to provide for extended shelf life. The bone in this form is usually very coarse and dry and is difficult to manipulate by the surgeon. One solution to use such freeze dried bone has been provided in the form of a commercially available product, GRAFTON(copyright), a registered trademark of Osteotech Inc., which is a simple mixture of glycerol and lyophilized, demineralized bone powder of a particle size in the range of 0.1 cm to 1.2 cm (1000 microns to 12,000 microns) as is disclosed in U.S. Pat. No. 5,073,373 forming a gel. Another version of this product from Osteotech, Inc. is a putty, which uses small bone fibers or shards produced by turning bone shafts on a lathe device to form shreds of bone. The small fibrous bone turnings created by the cutting tool are added to glycerol and form a swollen and tangled mass.
The GRAFTON(copyright) bone product works well to allow the surgeon to place the allograft bone material at the site. However, the carrier, glycerol has a very low molecular weight (92 Daltons) and is very soluble in water, the primary component of the blood which flows at the surgical site. Glycerol also experiences a marked reduction in viscosity when its temperature rises from room temperature (typically 22xc2x0 C. in an operating room) to the temperature of the patient""s tissue, typically 37xc2x0 C. This combination of high water solubility and reduced viscosity causes the allograft bone material to be xe2x80x9crunnyxe2x80x9d and to flow away from the site almost immediately after placement; which prevents the proper retention of the bone putty within the site as carefully placed by the surgeon.
These problems with GRAFTON(copyright) product have been attempted to be resolved by using a much larger particle size of allograft bone, specifically lamellae or slivers of bone created by milling or slicing the bone before mixing it with the glycerol carrier. This improves both the bulk viscosity and the handling characteristics of the mixture but still leaves the problem of the fast rate of dissipation of the carrier and some bone material due to the solubility of the glycerol carrier. The larger slivers of demineralized bone may also retard the development of new bone by the patient because the large bony lamellae do not pack as well as the smaller grainy particles of bone. This will leave more open space and could lengthen the time required to grow new bone and properly fill the defect. Another deficiency of using the bony lamellae is that the ends of the bony fragments are uneven and when packed into the surgical defect, leave uneven filaments of bone protruding out from the defect which can compromise the healing rate and present uneven surface areas of bone growth.
A recent version of GRAFTON(copyright) product uses relatively large demineralized particles in the carrier to create a heterogenous mixture which provides body or substance to the composition. This material is useful in filling larger defects where some degree of displacement resistance is need by the filler. Unfortunately this form of defect filler is not without problems in its surgical application. The glycerol carrier, common to all GRAFTON(copyright) product formulation is highly soluble in water. As previously noted, when applied in surgery, it is exposed to flowing blood, other body fluids and often, irrigation of the site by the surgeon, using large amounts of saline or sterile water. These fluids will wash away the glycerol and at least some of the demineralized bone matrix, resulting in a loss of the demineralized bone matrix at the site where it is needed.
Another new form from Regeneration Technologies, Inc.(copyright) utilizes corticocancellous chips dispersed in a thermoplastic demineralized bone matrix. Marketed as OpteForm 100 HT(trademark), it is a uniform particle size corticocancellous chip mass delivered in a thermoplastic polymer which must be warmed to 43-49xc2x0 C. to be malleable. After packing into the wound, it becomes solid after cooling to reach body temperature (37xc2x0 C.). This material uses uniformly sized chips which leave unfilled space between them, thus not providing a maximal amount of demineralized bone and retarding bone healing. Also, the need to warm the formulation before use is a considerable inconvenience in the operating room.
The prior art discloses a number of demineralized bone products. U.S. Pat. No. 5,290,558 discloses a flowable demineralized bone powder composition using a osteogenic bone powder with large particle size ranging from about 0.1 to about 1.2 cm. mixed with a low molecular weight polyhydroxy compound possessing from 2 to about 18 carbons including a number of classes of different compounds such as monosaccharides, disaccharides, water dispersible oligosaccharides and polysaccharides.
The advantages of using the bone particle sizes as disclosed in the U.S. Pat. No. 5,073,373 patent previously discussed were compromised by using bone lamellae in the shape of threads or filaments and still retaining the low molecular weight glycerol carrier. This later prior art is disclosed in U.S. Pat. Nos. 5,314,476 and 5,507,813 and the tissue forms described in these patents are known commercially as the GRAFTON(copyright) Putty and Flex, respectively.
The use of the very low molecular weight glycerol carrier also requires a very high concentration of glycerol to be used to achieve the bulk viscosity. Glycerol and other similar low molecular weight organic solvents are toxic and irritating to the surrounding tissues. Furthermore glycerol has been reported to be specifically neurotoxic and this problem is compounded when the concentration of glycerol is at the 20-95% level as disclosed in the U.S. Pat. No. 5,073,373 patent and the same is placed in a patient.
U.S. Pat. No. 5,356,629 discloses making a rigid gel in the nature of a bone cement to fill defects in bone by mixing biocompatible particles preferably polymethylmethacrylate coated with polyhydroxyethylmethacrylate in a matrix selected from a group which lists hyaluronic acid to obtain a molded semi-solid mass which can be suitably worked for implantation into bone. The hyaluronic acid can also be utilized in monomeric form or in polymeric form preferably having a molecular weight not greater than about one million Daltons. It is noted that the nonbioabsorbable material which can be used to form the biocompatible particles can be derived from xenograft bone, autologous bone, autogenous bone as well as other materials. The bioactive substance can also be an osteogenic agent such as demineralized bone powder, in addition to morselized cancellous bone, aspirated bone marrow and other autogenous bone sources. The average size of the particles employed is preferably about 0.1 to about 3.0 mm, more preferably about 0.2 to about 1.5 mm, and most preferably about 0.3 to about 1.0 mm. It is inferentially mentioned but not taught that particles having average sizes of about 7,000 to 8,000 microns, or even as small as about 100 to 700 microns can be used. However, the biocompatible particles used in this reference are used in a weight ranging from 35% to 70%. This is simply a cement used for implantation of hip prosthesis and is not used to promote bone growth.
U.S. Pat. No. 5,830,493 is directed toward a composite porous body (hyaluronic acid listed in a group of compounds) comprising a porous frame and a surface layer comprising a bioabsorbable polymer material formed on the surface. A bone morphogenetic protein (BMP) is carried on the surface and inside of the composite porous body. There is no demineralization of bone and the reference appears only to be relevant to show the addition of BMP to a bone forming graft.
Another attempt to solve the bone composition problem is shown in U.S. Pat. No. 4,172,128 which discloses demineralized bone material mixed with a carrier to reconstruct tooth or bone material by adding a mucopolysaccharide to a mineralized bone colloidal material. The composition is formed from a demineralized coarsely ground bone material, which may be derived from human bones and teeth, dissolved in a solvent forming a colloidal solution to which is added a physiologically inert polyhydroxy compound such as mucopolysaccharide or polyuronic acid in an amount which causes orientation when hydrogen ions or polyvalent metal ions are added to form a gel. The gel will be flowable at elevated temperatures above 35xc2x0 C. and will solidify when brought down to body temperature. Example 25 of the ""128 patent notes that mucopolysaccharides produce pronounced ionotropic effects and that hyaluronic acid is particularly responsible for spatial cross-linking. This bone gel is difficult to manufacture and requires a premolded gel form.
U.S. Pat. No. 4,191,747 teaches a bone defect treatment with coarsely ground, denatured bone meal freed from fat and ground into powder. The bone meal is mixed with a polysaccharide in a solution of saline and applied to the bone defect site.
Accordingly, the prior art as embodied in the glycerol and other carrier based technology to deliver demineralized allograft bone to a surgical osseous site is replete with problems and only partially addresses the problems inherent in correcting surgical defects.
The subject formulation is a complex mixture of demineralized and mineralized bone matrix and a viscous hydrogel having a high molecular weight material with a sodium based phosphate buffer acting as a carrier or delivery vehicle for the therapeutic agent, demineralized and mineralized bone matrix. The viscous formulation is designed to present the bone matrix, and its bone morphogenetic proteins (BMP). The macrostructure of the highly porous bone matrix itself serves both as an osteoconductive matrix and to signal the patient""s tissue and cells to initiate the growth of new bone (osteoinduction). The formulation can be used in contact with bleeding bone. This condition is created either from trauma or a surgical procedure, that may involve drilling, sawing, grinding or scraping the bone to achieve a bleeding condition. In surgery, the bone is traumatized or surgically cut exposing blood capillaries, Haversian canals (micro-channels in the bone), periosteum (the protective tissue lining around bone), muscle and other structures in the surgical site. Bleeding at the site is considered a favorable condition to enhance healing of the wound site by bringing to the site the patient""s own cytokines, i.e., proteins and other molecules which are the body""s mechanism to carry out the healing process. Any interference with the blood cell mechanism would be considered non-biocompatible and an adverse outcome.
The present invention, a bone putty with a useful bulk viscosity has been achieved by using a very high molecular weight class of soluble hydrogel biomaterial as a carrier for demineralized bone powder mixed with mineralized and/or demineralized larger bone chips and/or machined bone rods which can be mineralized or partially or fully demineralized. The use of high molecular weight hydrogels of 700,000 Daltons, preferably over one million Daltons allows the achievement of a very malleable high strength bone putty with only a 2-5% concentration of the hydrogel in the carrier. The balance of the carrier formulation is a sterile saline and sodium phosphate buffer which avoids the toxic problems with the high concentrations of the low molecular weight organic solvents of the prior art.
In order for the bone matrix to be osteoinductive, interference either from the traumatized cells or the formulation must be at a minimum, i.e., a biocompatible condition should be established and maintained. Several specific properties have been established in the formulation to create a functional and therapeutic material. These properties pertain to both physical characteristics and to the achieving of a biocompatible or physiologically friendly condition.
It can be seen that the prior art has attempted to replicate to some degree the bone putty obtained by the mixing of blood with bone particles without the problems of mixing the two together at the surgical site in non-controlled proportions and under time and space prohibitions.
The selection of high molecular weight hydrogels for the carrier allows the use of small particle size granules of demineralized allograft bone mixed together with larger chips of demineralized and/or mineralized bone and/or rods of mineralized and/or partially or fully demineralized bone. These composite materials pack better in the wound defect providing greater strength to the packed putty and induces new bone thereby allowing the bone defect to be remodeled into the natural bone of the patient.
It is an object of the invention to utilize demineralized powdered bone in a particle size that is useful to achieve the malleability characteristics that maximizes the amount of bone in the formulation in combination with larger mineralized or demineralized chips and/or mineralized or demineralized rod members to provide overall strength and initial durability to the composition.
It is an additional object of the invention to use a non toxic carrier for the bone particles and bone chips and/or bone rods which will not adversely impact on the patient.
It is also an object of the invention to create a bone defect material which can be easily handled by the physician and does not degenerate when contacting blood flow or irrigation at the surgical site.
It is another object of the invention to utilize demineralized powdered bone in a particle size which together with larger mineralized or demineralized chips and/or rod members that is useful to achieve the malleability characteristics that maximizes the amount of bone in the formulation without creating a gritty, less malleable characteristic.
It is an additional object of the invention to use a non toxic aqueous solution carrier with a sodium phosphate buffer for the respective bone elements to present the composition in a state of physiological osmolality (isotonic) at the wound site and provides a smooth bone surface.
It is also an object of the invention to create a bone defect material which can be easily handled by the physician and does not degenerate when contacting blood flow at the surgical site.
It is another object of the invention to create a bone defect material which does not interfere with healing at the wound site.
It is still another object of the invention to create a bone defect material which has a stable viscosity from 220 to 37xc2x0 C.
It is an additional object of the invention to create a bone defect material with a physiological pH of 7.4.
It is yet another object of the invention to use a sodium salt with the buffered, isotonic demineralized bone composition to aid in healing at the bone defect site.